The biological basis for functional loss after spinal cord injury is the elimination of nerve impulse transmission “up and down” the spinal cord. The basis for a partial functional recovery, independent of how old the injury is, is the restoration of such nerve impulses—in the case of the instant invention, by pharmacological means.
Mechanical damage to the nervous system of mammals results in sometimes irreversible functional deficits. Most functional deficits associated with trauma to both the Peripheral Nervous System (PNS) or Central Nervous System (CNS) result from damage to the nerve fiber or axon, blocking the flow of nerve impulse traffic along the nerve fiber. This may be due to a physical discontinuity in the cable produced by axotomy. The blockage may also occur where the membrane no longer functions as an ionic fence, and/or becomes focally demyelinated [Honmou, O. and Young, W. (1995) Traumatic injury to the spinal axons (Waxman, S. G., Kocsis, J. D., Stys, P. K., Eds.): The Axon, New York: Oxford UP, pp 480–503; Maxwell, W. L. (1996): Histopathological changes at central nodes of ravier after stretch-injury, Microscopy Research and Technique, 34:522–535; Maxwell, W. L., Watt, C., Graham, D I., Gennarelli, L A. (1993): Ultrastructural evidence of axonal shearing as a result of lateral acceleration of the head in non-human primates, Acta Neuropathol, 86:136–144; Maxwell, W. L., Graham, D. I. (1997): Loss of axonal microtubules and neurofilaments after stretch-injury to guinea pig optic nerve fibers, J Neurotrauma, 14:603–614; Blight, A R. (1993): Remyelination, Revascularization, and Recovery of Function in Experimental Spinal Cord Injury (Seil, F. J., Ed.): Advances in Neurobiology: Neural Injury and Regeneration, Vol. 59, New York, Raven Press, pp. 91–103]. In either case, functional deficits occur because of the break in nerve impulse conduction. Even the severe behavioral deficits associated with spinal cord injury is now understood to be largely due to the initial mechanical damage to white matter [Blight, A. R.: Morphometric analysis of a model of spinal cord injury in guinea pigs, with behavioral evidence of delayed secondary pathology, J. Neurolog. Sci., 103:156–171, 1991]. Delayed but progressive episodes of so-called “secondary injury” [Honmou and Young, W. (1995): Traumatic injury to the spinal axons (Waxman, S. G., Kocsis, J. D., Stys, P. K., Eds.): The Axon, New York: Oxford UP pp 480–503; Young, W. (1993): Secondary injury mechanisms in acute spinal cord injury, J. Emerg. Med., 11:13–22.] subsequently enlarge the lesion leading to the typical clinical picture of a cavitated contused spinal cord, and intractable behavioral loss.
Spinal cord injury is a compression injury to the cord even in clinical injuries experienced by humans. The popular notion that the spinal cord is “severed” is largely incorrect, as true anatomical transection of the spinal cord is quite rare in human injuries. After the injury, there is a variable amount—or “rind”—of spinal cord white matter left intact. However, this region of anatomically intact nerve fibers does not function. In particular, this local region (usually less than 1 vertebral segment in extent) does not conduct nerve impulses through the region of damage. This is believed to be due to demyelination, as well as other factors. The loss, or the reduced thickness of myelin, which insulates the nerve process, causes conduction blockage at the Nodes of Ranvier. This is because so-called “voltage gated” fast potassium channels are localized at paranodal regions in myelinated nerve fibers underneath an insulating layer of myelin. When myelin retracts or is lost after injury, the clusters of potassium channels are exposed to extracellular fluids and are also deprived of their electrical insulation. Potassium loss though these naked channels both increases the extracellular concentration of potassium, and helps extinguish a nerve impulse (actually a depolarization of this local nerve membrane). Indeed, it is well known that the extracellular microenvironment near a spinal injury is rich in potassium, which by itself dampens the ability of nervous tissue to function normally. Eidelberg, et al., (1975), Immediate consequences of spinal cord injury: Possible role of potassium in axonal conduction block, Surg Neurol 3:317–321.
Moreover, the loss of the electrical insulating capacity of myelin facilitates short circuit potassium current that aids in extinguishing the nerve impulse before it can begin to cross the nodal region. Blight A. R. (1993), “Remyelination, revascularization, and recovery of function in experimental spinal cord injury”, Seil F. J. (ed) Advances in neurobiology: Neural injury and regeneration (vol) 59 pp 91–103. Drugs that block this exodus of potassium from inside the nerve fiber to the outside milieu (so called channel blockers) are believed to be the biological basis for the restoration of action potential (or nerve impulse) conduction through spinal lesions associated with variable recoveries of functions in human patients. Hayes K. C., et al. (1993) Pre-clinical trial of 4-Aminopyridine in patients with chronic spinal cord injury, Paraplegia 31:216–224; Hayes K. C. (1994) 4-Aminopyridine and spinal cord injury: A review, Restor Neurol Neurosci 6:259–270; Hansebout R. R., Blight et al. (1993) 4-Aminopyridine in chronic spinal cord injury: A controlled, double-blind, crossover study in eight patients. J Neurotrauma 10:19–24. The only drug of this type, 4-Aminopyridine (the “time release” form of the drug is called Fampridine), has shown promise in restoring nerve function in paralyzed persons. However, clinically meaningful recoveries of function only occur in about 30% of the treated population, and in the balance, these recoveries are associated with numerous unwanted side effects that occur at the concentrations of the drug required. Such unacceptable side effects include dizziness mid loss of balance at one end of a scale—to the possibility of seizures at the other.
This problem is of such magnitude that infusions of 4 AP directly into the cerebrospinal fluid have been applied in dogs, Pratt K., et al., (1995) Plasma and cerebral spinal fluid concentrations of 4-Aminopyridine following intravenous injection and metered intrathecal delivery in canines, J Neurotrauma 12:23–39, and has been recently tried in six human patients. Halter J. A., et al. (2000) Intrathecal administration of 4-Aminopyridine in chronic spinal injured patients, Spinal Cord 12:7828–232. This would theoretically provide high concentrations of the drug directly at the spinal cord lesion, eliminating high concentrations in the blood. While such intrathecal administration is possible, it requires extensive and complicated surgery to implant special pumps and to cannulate the damaged spinal cord. The need exists, therefore, for improved compounds, pharmaceutical compositions, and methods that are useful in the treatment of spinal injury and that do not suffer from the aforementioned drawbacks. In particular, there is a need for compounds, compositions, and methods which will reduce the damaging effect of a traumatic injury to mammalian CNS tissue, especially spinal tissue, by in vivo treatment thereof.